A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-KB pathway

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like re-ceptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tis -sues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic ki-nase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhib-itor KIC-0101 that potently suppresses the NF-KB pathway and proinflammatory cytokine induction in vitro and in vivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-kB and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-kB pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoim-mune diseases and ibrutinib-resistant B-cell lymphomas.(c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

IRAK4 plays a key role in the TLR/MYD88 signaling pathway and is highly activated in rheumatoid arthritis tissues and ABC-DLBCL. IRAK4 activation promotes B-cell proliferation and lymphoma aggressiveness. We developed a dual IRAK4/PIM1 inhibitor, KIC-0101, which effectively suppresses the NF-KB pathway and proinflammatory cytokine induction in vitro and in vivo. KIC-0101 shows promising results in treating autoimmune diseases and ibrutinib-resistant B-cell lymphomas.